Short half-lived radioactive compounds are useful as imaging agents to diagnose cancers and abscesses. In the routine production of such imaging agents, safety and production considerations must be taken into account. It is advantageous to minimize contact time while ensuring quick and consistent production of the imaging agents.
There are generally two types of imaging procedures conducted. In positron emission tomography (PET), two beta rays emitted from the decaying radionuclide are detected. In single photon emission computed tomography (SPECT), one beta ray emitted from the decaying radionuclide is detected. PET provides a more exact location of tumors. However, SPECT is simpler and easier to use, and is therefore used more often.
Generally speaking, PET uses radio-compounds labeled with the positron-emitters such as 18F, 11C, 13N and 15O, SPECT uses radio compounds labeled with the single-photon-emitters such as 18F, 11C, 13N and 15O, although 75Br and 124I can also be used. SPECT, on the other hand, generally uses radionuclides that have more neutrons than protons, such as 67Ga, 77Br, 123I, 124I, 125I, 126I, 131I and 201TI.
In the art, glucose-based and amino acid-based compounds have been used as imaging agents. Amino acid-based compounds are more useful in analyzing tumor cells, due to their faster uptake and incorporation into protein synthesis. Of the amino acid-based compounds, 11C- and 18F-containing compounds have been used with success. 11C-containing radiolabeled amino acids suitable for imaging include, for example, L-[1-11C]leucine (Keen et al. J. Cereb. Blood Flow Metab. 1989 (9):429-45), L-[1-11C]tyrosine (Wiesel et al. J. Nucl. Med. 1991 (32):2041-49), L-[methyl-11C]methionine (Comar et al. Eur. J. Nucl. Med. 1976 (1):11-14) and L-[1-11C]methionine (Bolster et al. Appl. Radiat. Isot. 1986 (37):1069-70). However, 11C-containing radiolabeled amino acids have limited applicability, due to the short half-life of 11C (T1/2 =20 min.). Therefore, great effort was directed toward the synthesis and evaluation of other radionuclides, such as those listed above. Two 18F-containing radiolabeled amino acids, 4-[18F]fluoro-L-phenylalanine and 2-[18F]fluoro-L-tyrosine, exhibit protein incorporation, but can only be synthesized with uncorrected yields less than 5%. See Arnstein et al. Biochem. J. 1984 (1):340-46 and Coenen et al. Radioisot. Klinik. Forschung 1988 (18):402-40.
More recently, position 2- and 3-L-[18F]fluoro-xcex1-methyl tyrosine have been synthesized by electrophilic substitution (Tomiyoshi et al. Nucl. Med. Commun. 1997 (18):169-75). Unfortunately, the radiochemical yield from such a production is low. Another more recent compound to be synthesized is o-(2-[18F]fluoroethyl)-L-tyrosine (Wester et al. J. Nucl. Med. 1999 (40):205-212). This paper describes the synthesis of the target compound, using a nucleophilic reaction, in a 40-60% yield. However, the reaction requires a two-step synthesis.
An object of the present invention is to develop new imaging agents suitable for use in PET and SPECT and which overcome the disadvantages of known compounds.
Another object of the present invention is to provide a method of manufacturing such compounds via the nucleophilic route using a one-step synthesis.
A further object of the invention is to provide precursors useful for manufacturing the new imaging agents of the invention.
These objects are achieved by the present invention.
The present invention includes compounds of formula (I), or pharmaceutically acceptable salts thereof: 
wherein
the C marked with an asterisk represents a chiral center and the compound is present in the L-form, the D-form or as a racemic mixture;
R1 is selected from the group consisting of a single bond, phenyl, and a group of formula (a), (b), (c) or (d) 
The present invention also includes compounds of formula (II), which are useful for preparing the compounds of formula (I): 
wherein
R1 is the same as indicated for the compounds of formula (I);
R2 is H or a group xe2x80x94R3xe2x80x94Oxe2x80x94R4, wherein R3 is C1-C7 alkyl and R4 is H or a leaving group, preferably a sulfonyl group such as tosyl, trifyl, mesyl, trimsyl, tripsyl, brosyl or nosyl;
PG1 is a carboxyl protecting group; and
PG2 is an amino protecting group.
The present invention also includes a method of synthesizing compounds of formula (I) by reacting a compound of formula (IIc): 
wherein R1, R2, PG1 and PG2 are the same as indicated for the compounds of formula (I), and R3 is a leaving group, preferably a sulfonyl group such as tosyl, trifyl, mesyl, trimsyl, tripsyl, brosyl or nosyl,
with a salt of RE, where RE is the same as indicated for the compounds of formula I, to produce a compound of formula (Ia): 
wherein R1, R2, RE, PG1 and PG2 are the same as above; and removing the protecting groups.
In this invention, compounds of formula I have been developed: 
wherein
the C marked with an asterisk represents a chiral center and the compound is present in the L-form, the D-form or as a racemic mixture; R1 is selected from the group consisting of a single bond, phenyl, and a group of formula (a), (b), (c) or (d) 
R2 is C1-C7 alkyl; and
RE is selected from the group consisting of 11C, 13N, 15O, 18F, 67Ga, 75Br, 77Br, 123I, 124I, 125I, 126I, 131I, and 201TI, preferably 123I, 125I, and 18F.
Preferably, R1 is phenyl. When R1 is phenyl, the xe2x80x94Oxe2x80x94R2xe2x80x94RE group can be para, meta or ortho the CH2 group. It is preferred that the xe2x80x94Oxe2x80x94R2xe2x80x94RE group is para the CH2 group.
R2 is preferably C2-C6 alkyl, more preferably C2-C5 alkyl. It is most preferable that R2 is propyl.
The compounds of formula (I) contain a chiral center at the xcex1-C. The compounds of the invention can therefore be present in the L-form, the D-form, or as a racemic mixture. It is preferred that the compounds be present in the L-form.
The present invention also includes compounds of formula (II): 
wherein
R1 is the same as indicated for the compounds of formula (I);
R2 is H or a group xe2x80x94R3xe2x80x94Oxe2x80x94R4, wherein R3 is C1-C7 alkyl and R4 is H or a leaving group, preferably a sulfonyl group such as tosyl, trifyl, mesyl, trimsyl, tripsyl, brosyl or nosyl;
PG1 is a carboxyl protecting group; and
PG2 is an amino protecting group.
The compounds of formula (II) are useful as intermediates in the preparation of compounds of formula (I).
More specifically, the compounds of formula (II) may be divided into subgroups (IIa), (IIb) and (IIc): 
which are important intermediates in the preparation of compounds of formula (I),
wherein in each case
R1 and R2 are the same as indicated for the compounds of formula (I);
R3 is a leaving group, preferably a sulfonyl group such as tosyl, trifyl, mesyl, trimsyl, tripsyl, brosyl or nosyl;
PG1 is a carboxyl protecting group; and
PG2 is an amino protecting group.
As noted above, the leaving groups for compounds of formula (II) are preferably sulfonyl groups, however any suitable leaving group can be used, as known to those of ordinary skill in the art. Especially preferred are tosyl, trifyl, mesyl, trimsyl, tripsyl, brosyl or nosyl, with tosyl, trifyl and mesyl being more preferred and tosyl being most preferred.
The protecting groups (PG1 and PG2) can be any suitable carboxyl protecting group and amino protecting group, as known to those of ordinary skill in the art. Reference is made to xe2x80x9cProtective Groups in Organic Chemistry,xe2x80x9d ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene and P. G. M. Wuts, xe2x80x9cProtective Groups in Organic Synthesis,xe2x80x9d John Wiley and Sons, 1991, each incorporated by reference. PG1 may be, for example, an alkyl group such as methyl, ethyl or propyl. PG2 may be, for example, a Boc group.
Generally, the reaction scheme for preparing compounds of formula (I) is as follows. A starting compound of formula (III): 
wherein R1 and PG1 are the same as indicated for the compounds if formula (I), such as xcex1-methyl tyrosine C1-C3 alkyl ester, xcex1-methyl serine C1-C3 alkyl ester or xcex1-methyl hydroxy-tryptophan C1-C3 alkyl ester,
is reacted in a suitable solvent with a compound providing a suitable protecting group PG2, such as di-t-butyl dicarbonate (which provides a Boc group), to protect the amine, giving the compound of formula (IIa).
The compound of formula (IIa) is thereafter reacted in a suitable solvent with a halogenated C1-C7 alkanol, to give the compound of formula (IIb).
The compound of formula (IIb) is thereafter reacted in a suitable solvent with a halogenated leaving group, such as halogen-tosyl, to give the compound of formula (IIc).
The compound of formula (IIc) is reacted in a suitable solvent with a salt of RE, as defined above, such as K-18F, to give the compound of formula (Ia). The compound of formula (Ia) is converted into the compound of formula (I) by removing the protecting groups (PG1 and PG2), for example by using TFA.
In the exemplified embodiment, 3-[18F]fluoropropyl-xcex1-methyl tyrosine, the radiochemical yield for the compound of the invention was much higher than 11C- and 18F-labeled amino acids synthesized using an electrophilic process. In addition, the compounds of the invention are stable and show high uptake in tumors. The compounds of the invention are useful to differentiate the degree of malignancy of tumors (e.g., brain, breast, prostate, colon, lung, liver, pancreas, gastric, lymphoma, uterine, cervical, extremitis, sarcoma and melanoma). The compounds of the invention are also useful to image neurological disorders (e.g. Alzheimer""s, Huntington""s), abscess, inflammation and infectious diseases. Suitable dosages are known or could be easily determined by those of ordinary skill in the art.